Invasive aspergillosis (IA) is caused by the mould Aspergillus fumigatus and is an understudied disease of growing significance that causes over 3,500 deaths in the United States annually. The spectrum of patients susceptible to A. fumigatus infections is also dramatically increasing with the development of new medical technologies. Currently, our understanding of the mechanisms utilized by this common mould to cause disease is limited. Though it is likely that A. fumigatus encounters significant environmental stress during IA, how the fungus adapts to micro-environments found in vivo at sites of infection is not fully understood. We have discovered that A. fumigatus encounters significant hypoxia during infection. Importantly, we have discovered that adaptation to hypoxia is genetically regulated in this mould and required for fungal virulence. Thus, the long-term objective of this proposal is to define the molecular mechanisms utilized by this fungus to adapt to hypoxia and cause disease in immunocompromised patients. This may lead to development of novel therapeutic interventions for IA. This proposal has three specific aims designed to define the molecular mechanism of hypoxia adaptation as mediated by a sterol-regulatory element binding protein (SREBP), SrbA, that mediates hypoxia adaptation and fungal virulence in A. fumigatus. In aim 1, we will define where and when SrbA is activated in A. fumigatus establishing the first part of a model of SrbA mediated hypoxia adaptation in A. fumigatus. In aim 2, we will identify and characterize the key players that interact with SrbA and likely regulate its activity adding the second regulatory layer to our model. In aim 3, the key downstream effectors of SrbA that mediate adaptation to hypoxia by A. fumigatus will be identified and characterized. Completion of these 3 aims will offer much needed insights into the mechanisms of a novel virulence attribute of A. fumigatus and lay the foundation for a model of SREBP signaling in a pathogenic mould for the first time. Investigations in these specific aims will also provide additional targets for future studies to elucidate mechanisms of hypoxia adaptation that may be applicable to a broad-spectrum of pathogenic moulds. PUBLIC HEALTH RELEVANCE: Lethal infections by common moulds are becoming increasingly common with advances in medical technologies. Treatment options for these infections are very limited, and new therapeutic interventions are urgently needed. This proposal seeks to discover new therapeutic options to treat invasive aspergillosis caused by the filamentous mould Aspergillus fumigatus.